Process for the preparation of nicotinic acid esters of steroid compounds



United States atent 3 167 544 PROCESS FOR TIE PlEPARATlQN F NECOTllNlCACID ESTERS 0F STERGID CQMPOUNDS Joachim Heider and Dietrich Jerchel,Biberach (Rise),

Germany, assignors to Boehringer Ingelheim G.m.b.H.,

Ingelheim am Rhein, Germany, a corporation of Germany N0 Drawing. FiledDec. 17, 1963, Ser. No. 331,124

3 Claims. (Cl. 260-2395) This invention relates to steroid esters aswell as to a novel method of preparing such steroid esters.

More particularly, the present invention relates to steroid esters ofthe formula hydroxyl group, the grouping Y -O\ /CH&

I O CHa 40 and Z is --CH 0 g or. a carbon-to-carbon bond,

as well as to a novel process which makes it possible to prepare suchsteroid esters in one continuous sequence of reaction steps, that is,without having to isolate the intermediate products.

The preparation of nicotinic acid esters of cortisone, hydrocortisone,prednisone and prednisolone is already known, as such, from Monatsheftefiir Chemie 92, 672- 676 (1961). Further, in copending US. applicationSer. No. 216,738, filed August 14, 1962, the preparation of, inter alia,esters of 9a,-fiuoro-hydrocortisone, dexameth- 'asone and triamcinolonewith pyridyl-carboxylic acids and picolyl-carboxylic acids is described.In both instances the preparation of the esters is effected by knownesterification processes, preferably by reaction of the steroid.alcohols with the corresponding carboxylic acid halides or anhydrides,

However, in these known processes it is initially necessary to prepare,in a separate reaction step, a reactive derivative of an acid of theformula wherein Z has the same meanings as in Formula I. The

ice

preparation of such reactive derivatives is known to be inconvenientand, in most instances, proceeds with only moderate yields; in someinstances, for example, when Z in the above 'formula II is -CH or orwhen the group --Z--COOH is in the 2-position, the preparation of suchreactive derivatives is even practically impossible. Thus, steroidesters of these acids could be obtained by the .known processess onlythrough the considerably more involved reaction of a 21-halo steroidwith a salt of the particular acid.

Moreover, in the case of various slowly reacting steroid alcohols, forinstance, cortisone or prednisone, the known esterification processesrequired more severe conditions; for instance, reaction in the presenceof phosphorus oxychloride or molten anhydride. Under these conditionsthe sensitive corticosteroids form side products which can be removedagain only with great difficulty.

We have now discovered that all of the esters of the above-indicatedgeneral Formula I can be obtained at room temperature in one reactionstep and with yields up to and more, if steroid alcohols of the formulaformulas:

it I soon 2[ I N N (IV) m-zooon (III) In theseformulas R R R,, X, Y andZ meanings as in Formula I above;

have the same 3 The sequence of reactions is carried out at roomtemperature, advantageously in an inert organic solvent, preferably intetrahydrofuran, because this solvent has the most favorable solutionproperties. Initially, four mols of imidazole are reacted with one molof thionylchloride at room temperature; the precipitatedirnidazolehydrochloride is separated by vacuum filtration,advantageously in the atmosphere of an inert gas, but it can also berecovered together with the irnidazole which is formed after conclusionof the entire sequence of reac tions. An acid of the Formula II is thenadded to the solution of the N,N'-thionyl-di-imidazole formed by thereaction, and the mixture is shaken at room temperature; after abouthalf an hour a steroid alcohol of the Formula III is then added and themixture is thereafter shaken at room temperature for -24 hours,preferably in the presence of an imidazole salt as a catalyst. The acid11 and the steroid alcohol III are preferably used in equimolar amounts,and l-3 mols of the N,N'-thionyl-di-imidizaole, preferably 2.7 mols, areused per mol of the two reactants. The point of time when the reactionhas gone to completion may readily be determined by thin-filmchromatography. I

The reaction mixture can be very simply worked up by distilling off theinert solvent under reduced pressure and triturating the residue withwater; the desired ester then precipitates out and may be separated byvacuum filtration and purified by recrystallization.'

quantitatively from the aqueous filtrate. The yield of pure steroidester is on the average 60-80% of theory or more.

The following examples further illustrate the invention and will enableothers skilled in the art to understand it more completely. It should beunderstood, however, that the present invention is not limited to theparticular examples given below.

For the sake of simplicity, the following non-proprietary names havebeen used:

Hydrocortisone for 1113,17oc,2 ltrihydroxypre'gnl-ene- 3,20-dione,

Prednis'one for 17a,2l-dihydroxy-pregna-1,4-diene 3,11,20-trione,

Prednisolone for l173,17a,2l-trihydroxy-pregna-l,4-

diene-3,20-dione, 9a-tluorohydrocortisone for 9a-fluoro-l1;3,17a,2l-

trihydroxy-pregn-4-ene-3,ZO-dione,

Dexamethasone for 9a-flu0ro-l6a-methyl-11B,17a,2ltrihydroxy-pregna-l,4-diene-3,20-dione,

and

Triamcinolone for 9a-fluoro'1lfi,16a,17a,21-tetrahydroxy-pregna-l,4-diene-3,20-dione.

EXAMPLE 1 Preparation of pyridyl-2-carboxylic acid-(hydrocortisone-21)-ester 0.5 gm. of hydrocortisone. About 0.07 mol of sodium imidazolewas added as a catalyst. The reaction mix 4 having a melting point of243-246 C. (decomposition) was obtained. It was identified to be thesteroid ester of the formula '---0H no? boxylicacid-(hydrocortisone-Zl)-ester of the formula The imidazole originallyemployed can be recovered virtually i CHzO-b I no? CH3 0: if

drocortisone. The product was a white substance having a melting pointof 210-212 C. (decomposition). 1

EXAMPLE 3 Preparation of pyrz'a'yI-4-carbovcylic acid-(hyarocortirone-21 )-ester 1 was obtained after 20 hours of shaking at room temperaturewas then shaken for 21 hours at room temperature.

On the basis of thin-film chromatographic determination, the reactionhad gone to completion after this time. After evaporation of thereaction solution in a rotation evaporator the residue was'trituratedwith water, and after separating the undissolved portion byvacuum filtration it was recrystallized'from a mixture ofethanol andwater. 0.5 gm. (77.6% oftheory) of a White substance ture from pyridy14-carboxylic acid and hydrocortisone- The white product had-amelting'point of- 2-35 12 37 Cf.

(decomposition). ,7

.i EXAMPLEAQ Pre mzratioa of V pyridyl-3-gly0xylicacid-(hydrocortisorie- T '2I.)-ester .of N,N'-thionyl-diimida zole intet'rahydrofuran, was ad- I mixed with 0.55 gm.0f'pyridyl-3-glyoxylicacid and 0.5

gm. of hydrocortisone, as described in Example 1. After a reactionperiod of 6 hours and Working up the reaction mixture as described. inExarnple l, 0.4 gm. (59% of theory) of a substance having a meltingpoint of 209-211 C. (decomposition) was obtained. It was identified tobe the steroid ester of the formula cm 0 CHz-O-(iL-J- EXAMPLEPreparation of pyridyl-S-acetic acid-(hydrocortisone- 21)-ester 0.27 cc.of thionylchloride, 0.5 gm. of pyridyl-3-acetic acid and 0.5 gm. ofhydrocortisone were reacted with a solution of 1 gm. of imidazole intetrahydrofuran in a manner analogous to that described in Example 1,and the reaction mixture was worked up. 0.55 gm. (82.6% of theory) of asubstance having a melting point of 236- 238 C. (decomposition) wasobtained. It was identitied to be the steroid ester of the formula anyEXAMPLE 6 Preparation of pyridyl-Z-carboxylic acid-(predm'solone-ZJ')-ester The yield was 65% of theory.

EXAMPLE 7 Preparation of pyridyl-4-carb0xylic acid-(prednisolone-ZI-ester 0.54 cc. of thionylchloride, 0.45 gm. of isonicotinic acid and0.5 gm. of prednisolone were reacted for 56 hours at room temperaturewith a solution of 2 gm. of imidazole in tetrahydrofuran in a manneranalogous to that described in Example 1, and the reaction mixture wasworked up. The product had-a melting point of 240-243 It was identifiedto be the steroid 0 t 3 CH -O- N (i=0 C. (decomposition). ester of theformula EXAMPLE 8 Preparation of pyridyl-3-acetic acid-(prednisolone-Z]-ester A solution of 1 gm. of imidazole in tetrahydrofuran, 0.27 cc. ofthionylchloride, 0.5 gm. of pyridy1-3-acetic acid and 0.5 gm. ofprednisolone were reacted for 16 hours at room temperature in a manneranalogous to that described in Example 1, and the reaction mixture wasworked up. The product had a melting point of 239-241 C.(decomposition). It was identified to be the steroid ester of theformula ---0H no? EXAMPLE 9 Preparation of pyridyl-Z-carboxylicacid-(dexamethasone-Z] -ester A solution of 0.5 gm. of imidazole intetrahydrofuran, 0.14 cc. of thionylchloride, 0.12 gm. ofpyridyl-Z-carboxylic acid and 0.25 gm. of dexamethasone were reacted for20 hours at 40 C. in a manner analogous to that described in Example 1,and the reaction mixture was Worked up. I The product had a meltingpoint of 254 C. It was identified to be the steroid ester of the formulaL--OH no- Torn EXAMPLE 10 Preparation of pyridyl-Z-carboxylic acid-(triamcinolone-21 -ester A solution of 0.5 gm. of imidazole intetrahydrofuran was reacted with 0.14 cc. of thionylchloride, 0.23 gm.of pyridyl-2-carboxylic acid and 0.25 gm. of triamcinolone for 20 hoursat 40 C. in a manner analogous to that described in Example 1, and thereaction mixture was Worked up. The product had a melting point of 207C.

. 7 It was identified to be the steroid ester of the formula CH3 J CHOil l 2 =0 '---on HO-(\: ]-OH EXAMPLE 11 Preparation ofpyridyl-3-carb0xylic acid-(prednisolone-ZZ -ester A solution of 0.38 gm.of imidazole in 45 cc. of tetrahydrofuran was admixed with 0. 4 gm. ofpyridy1-3-carboxylic acid chloride. After separating by vacuumfiltration the imidazole-hydrochloride which had precipitated, 0.5 gm.of prednisolone was added to the filtrate which containedN-nicotinyl-imidazolide. After 16 hours of standing at room temperaturethe reaction mixture was admixed with a solution consisting of 1 gm. ofimidazole in tetrahydrofuran, 0.3 cc. of thionylchloride and 0.45 gm. ofnicotinic acid, and the resulting mixture was maintained at 40 C. for anadditional 60 hours. Upon working up the reaction mixture as describedin Example 1, a White substance having a melting point of 218-221 C. wasobtained. It was identified to be the steroid ester of the formula on OHn-O-EL- The yield was 32% of theory.

EXAMPLE 12 Preparation of pyridyl-Z-carboxylic acid-(triamcin0l0ne-16,17-acet0nide-2l) -ester g the formula Theyieldwas 32% of theory.

8 EXAMPLE 13 Preparation of pyridyl-3'acetic acid-(dexdmethasone-ZI)ester gm. of pyridyl-3-acetic acid and 0.25 gm. of dexamethasome in amanner analogous to that described in Example 1, and the reactionmixture was Worked up after 20 days of standing. The reaction productwas recrystallized from a mixture of ethanol and Water. The whitesubstance obtained thereby had a melting point of 128-131 C.(decomposition). It was identified to be the steroid ester of theformula "011 Ha I Q /g\/ EXAMPLE 14 Preparation of isonicolinicacid-(cortisone 21)-ester A solution of 1 gm. of imidazole in 45 cc. oftetrahydrofuran was admixed with 0.27 cc. of thionylchloride, 0.45 gm.of is'onicotinic acid, 0.25 gm. of cortisone and 0.6 cc. of sodiumimidazole in a manner analogous to that described in Example 1, andafter 15 hours of standing the reaction mixture was worked up. The whitereaction product had a melting point of 137139 C. It was identified tobe the steroid ester of the formula 6:0 0 l iii The yield was 61.8% oftheory.

ester of the formula QH2O-(JJ;- N 7 (i=0 2 l The yield was 58.6% oftheory.

9. EXAMPLE 16 Preparation of pyridyl-S-glyoxylic acid-(prednisolone-21)-ester A solution of 1 gm. of imidazole in tetrahydrofuran wasreacted at room temperature for 16 hours with 0.27 cc. ofthionylchloride, 0.55 gm. of pyridyl-3-glyoxylic acid and 0.5 gm. ofprednisolone in a manner analogous to that described in Example 1, andthe reaction mixture was worked up. After recrystallization from'aqueousethanol, the reaction product hadameltingpointof 212 C.

(decomposition). It was identified to be the steroid ester I of theformula 0 CH3 capo-iii!- 1 '---on HO- EXAMPLE 17 Preparation ofpyridyl-S-acetic acid-(9'a-flu0rohydr0c0rtisane-ZI -ester A mixture of 2gm. of imidazole dissolved in tetrahydrofuran, 0.54 gm. ofthionylchloride, 0.5 gm. of 9afiuorohydrocortiso-ne and 1 gm. ofpyridyl-3-acetic acid was shaken for 30h0urs at.25 C., and-the reactionmixture was then worked up as described in Example 1. The reactionproduct-had a melting point 'of 145 C. It was identified to he thesteroid ester of the formula The yield was-64% of'theory.

EXAMPLE 18 Preparation of pyrz'dyl-S-acetic acid-(triamcinolone- 16a,1 7'a-acetonide-Zl -ester A mixture of 0.43 gm. oftriamcinolone-16oz,17a-ace-' tonide and 1 gm. of pyridyl-3 acetic acidwas reacted for 24 hours at room temperature in a manner analogous tothat described in Example 1, and the reaction mixture was worked up. Thereaction product had a melting point of 284 C. It was identified to bethesteroid ester of the The yield was 74% of theory.

i o EXAMPLE 19 Preparation of isonicotinic acid-(dexamethasone- 21-ester A mixture of 0.25 gm. of dexamethasone and 0.13 gm. ofisonicotinic acid was reacted for 24 hours at room temperature in amanner analogous to that described in Example 1, and the reactionmixture was worked up. The reaction product had a melting point of 256C. It was identified to be the steroid ester of the formula CH3 ifgramme-4 Nj The yield was 88.8% of theory.

EXAMPLE 20 Preparation of pyridyl-3-carbovcylic acid-(dexamethasone-Z]-ester A mixture of 0.25 gm. of dexamethasone and 0.13 gm. ofpyridyl-3-carboxylic acid was reacted for 24 hours at room temperaturein a manner analogous to that described in Example 1, and the reactionmixture was then worked up. The reaction product had a melting point of257 C. It was identified to be the steroid ester of the formula Theyield was 81% of theory.

The steroid esters prepared by the novel process according to thepresent invention have useful pharmacodyuamic properties. Moreparticularly, they exhibit highly eifec tive antiphlogistic activities.

While the present invention has been illustrated with the aid ofcertainspecific embodiments thereof, it will be readily apparent to othersskilled in the art that the invention is not limited to those specificembodiments, and that various changes and modifications maybe madewithout departing fr'omthe spirit of the invention or the scope of theappended claims.

We claim: 1. The method of preparing a steroid ester of the for- 1 1hydrogen and, together with each other, a double bond, R3 is selectedfrom the group consisting of and X is selected from the group consistingof hydrogen and fluorine, Y is selected from the group consisting ofhydrogen, hydroxyl, methyl and, together with the 17a-OH,

0 CH -0 CHa and Z is selected from the group consisting ofcarbon-tocarbon bond, CH and 0 &

which comprises reacting N,N'-thiony1-di-imidazole with apiperidyl-carboxylic acid of the formula Z-COOH wherein Z has themeanings defined above, to form an imidazolide of the formula wherein Zhas the meanings defined above, and reacting said imidazolide with asteroid alcohol of the formula CH OH HO- --Y CHa wherein R R R X and Yhave the meanings defined above, and recovering the reaction product.

2.'The method of preparing a steroid esterof the formula wherein V 7 Rand R are selectedfrom the group consisting of hydrogen and, togetherwith each other, a double bond, 7 R is selected from the groupconsisting of =0 and which comprises reacting N,N'-thionyl-di-irnidazoleat room temperature with a piperidyl-carboxylic acid of the formulawherein Z has the meanings defined above, to form an imidazolide of theformula a wherein Z has the meanings defined above, and reacting saidimidazolide at room temperature and in the presence of an alkali metalsalt of imidazole and an inert solvent with a steroid alcohol of theformula Ont-0H wherein R R R X and Y have the meanings define above, andrecovering the reaction product. a

3. The method of preparing a steroid ester of the for- R and R areselected from the group consisting of hydrogen and, together with eachother, a double bond, I R; is selected from the group consisting of =0and X is selected from the group consisting of hydrogen and fluorine, Iv i 13 Y is selected from the group consisting of hydrogen, hydroxyl,methyl and, together with the 17a-OH,

and Z is selected from the group consisting of carbon-tocarbon bond, CHand which comprises reacting N,N'-thionyl-di-imidazole at roomtemperature with a piperidyl-carboxylic acid of the formula fi z-o 0 OH\N wherein Z has the meanings defined above, to form an imidazolide ofthe formula wherein Z has the meanings defined above, and reacting saidimidaz-olide at room temperature and in the presence of an alkali metalsalt of imidazole and a tetrahydrofuran with a steroid alcohol of theformula No references cited.

1. THE METHOD OF PREPARING A STEROID ESTER OF THE FORMULA